Relationship between cytotoxicity,drug accumulation,DNA damage and repair of human ovarian cancer cells treated with doxorubicin: modulation by the tiapamil analog RO11-2933

Summary The effect ofN-(3,4-dimethoxyphenyl)N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 M as compared with 10 M verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic.Abbreviations RO11-2933 N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m-dithiane-2-propylamine hydrochloride - DOX doxorubicin-HCl - SSBs single-strand breaks - MDR multidrug resistance This work was supported in part by CA 18420 and CA 21071     

Depolarization thresholds for hippocampal damage, ischemic preconditioning, and changes in gene expression after global ischemia in the rat

Induced ischemic tolerance in rat hippocampus was investigated in a forebrain ischemia model of repeated 4-vessel occlusion (4-VO). Ischemic insult variability was reduced by the use of dc potential measurements to determine the duration of ischemic depolarization in hippocampus. The results demonstrate a depolarization threshold for ischemic injury to CA1 neurons of 4-6 min and a window for optimal preconditioning of 2.5-3.5 min. Levels of induced mRNAs encoding hsp72 and several immediate-early genes were also shown to vary with depolarization interval. Immediate-early genes were maximally induced after depolarization periods inducing optimal preconditioning, while hsp72 expression increased with insult severity over the range leading to neuron loss. These results are similar to those obtained in gerbil studies indicating that preconditioning does not require large increases in hsp72 expression, and demonstrate the fundamental comparability of rodent global ischemia models when monitored by this approach.     

Multicenter assessment of ultrasound of the spermatic cord in children with acute scrotum

PURPOSE: Intravaginal or extravaginal spermatic cord torsion is a diagnostic challenge for the surgeon and radiologist. Color Doppler sonography can be inaccurate, leading to dangerous false-negative results. To date, no single reliable test has been able to provide 100% diagnostic accuracy. The direct visualization of the twisted cord during emergency high resolution ultrasonography has been proposed to avoid systematic and abusive surgical exploration. The aim of this multicenter study was to assess the validity and reproducibility of high resolution ultrasonography based management of acute scrotum in children. MATERIALS AND METHODS: A total of 919 patients from 11 European university hospitals underwent color Doppler sonography and high resolution ultrasonography for acute scrotum between 1992 and 2005. The spermatic cord was studied along its complete length to detect a spiral twist. The surgical findings were correlated with the preoperative results. RESULTS: A total of 208 patients had spermatic cord torsion proved at surgery. Intratesticular vascularization was absent in the affected testis in only 158 cases (76%). In contrast, high resolution ultrasonography detected the twist as a snail shell-shaped mass, measuring 7 to 33 mm, in 199 patients (96%). High resolution ultrasonography revealed a linear cord for all other causes of acute scrotum (711 patients) with a specificity of 99%. The radiologist training level was the best predictive factor of high resolution ultrasonography reliability (p <0.05). CONCLUSIONS: High resolution ultrasonography based management of acute scrotum is reliable and reproducible. Thanks to its high sensitivity and specificity for the diagnosis of spermatic cord torsion, high resolution ultrasonography can significantly improve the management of acute scrotum in children.     

Cystic undifferentiated sarcoma of liver in children: a pitfall diagnosis in endemic hydatidosis areas

Undifferentiated (embryonal) sarcoma (UES) of the liver is a very rare pediatric neoplasm with an aggressive behavior. Multimodal treatment including complete surgical resection and chemotherapy has improved survival.We report a case of UES occurring in a 15-year-old female. Radiographic findings showed a multicystic mass appearance. The diagnosis of hydatid cyst was initially presumed. A complete tumor resection after 3 cycles of chemotherapy was performed. Histologically, only 20% of tumor necrosis was noted. Adjuvant chemotherapy was instituted. She remained well at 11 months of follow-up.Cystic appearance is a usual finding in UES. Differential diagnosis with hydatid cyst may be problematic in endemic hydatidosis areas.     

Surgical management of a circumflex aneurysm with fistula to the coronary sinus

We report the successful management of a circumflex coronary artery aneurysm with fistula to the coronary sinus. Our strategy aimed at closing the fistula and grafting the obtuse marginal artery. The calcified aneurysm was left intact, and showed secondary thrombus formation on the postoperative angiogram.     

Intraperitoneal mesh prosthesis metastasis from pancreatic cancer,after laparoscopic hernia repair

Introduction There are very few case reports of metastasis on a mesh prosthesis following laparoscopic hernia repair in the literature and its incidence is completely unknown.

Case report A 76-year-old male patient presented in December 2013 with a suspicious malignant lesion of the pancreatic tail on the MRI. He was also complaining of a painful mass in the right para-rectal area. An exploratory laparoscopy performed in December 2013 revealed microscopic whitish peritoneal implants in the left hypochondrium and a massive metastasis involving a mesh prosthesis placed é years before in the right para-rectal area. The pathology report of biopsies of the mesh confirmed a metastasis compatible with a pancreatic tumor.

Discussion Possible modes of metastasis and limited published data to date on mesh prosthesis metastasis are presented. This situation can be assimilated to port-site metastasis after laparoscopy.

Conclusion A mesh prosthesis metastasis after laparoscopic hernia repair is very rare.     

Congenital heart disease, maternal age and parental consanguinity in children with Down's syndrome

OBJECTIVE: Analyze the role of parental consanguinity and/or maternal age on the occurrence of congenital cardiac anomalies in infants with Down's syndrome (DS). MATERIAL AND METHODS: A large group of patients with or without congenital heart disease, registered between May 1st, 1999 and June 30th, 2006, at the National Register of Paediatric and Congenital Heart Disease, Lebanese Society of Cardiology. 217 children with DS have been enrolled over this period. Group I: DS with cardiac anomalies (n:119). Group II: DS without cardiac anomalies (n:98). The consanguinity rate was compared to a study made in 2000 by UNICEF in Lebanon, in which the consanguinity rate was 14.9% of 1st degree cousins and 25% of all degrees together. RESULTS: Congenital cardiac anomalies were found in 54.2% of babies with DS. First degree cousins in both groups I and II was 143% (close to the general population), and it was lower in group I compared to group II (11.8% and 17.3% respectively ; p = 0.205) ; this difference was not statistically significant for all degrees together. Maternal age ranged from 20 to 47 years, with a mean of 29.5 +/- 5.3 years. The risk of congenital cardiac anomaly was greater (p < 0.05) when maternal age was equal or below 32 years. As in the international literature, complete atrioventricular canal and ventricular septal defect were the most frequent cardiac anomalies. CONCLUSION: In children with DS, the risk of congenital cardiac anomalies was not associated with the parents consanguinity. Maternal age above 32 years seem to be associated with a lesser occurrence of congenital cardiac anomaly in children with DS.     

Extraskeletal neuroectodermal tumour of the vagina: a single case report and review

Abstract  A case report and review of an extraskeletal neuroectodermal tumour of the vagina. Background  Ewing’s sarcoma (ES) and primitive neuroectodermal tumours (PNETs) account for approximately 6–10% of primary malignant bone tumours and, following osteosarcoma, are the second most common group of bone sarcomas in children. Ewing’s sarcoma rarely affects the genitourinary tract. Case summary  We report a rare case of extraskeletal Ewing’s sarcoma diagnosed in a 47-year-old Indian woman presenting with a simple cystic lesion in the posterior wall of the vagina. The histopathology revealed a rare presentation of a primitive malignant extraskeletal neuroectodermal tumour. Conclusion  As our PubMed review found only six previously reported cases of vaginal extraskeletal Ewing’s sarcoma. Presentation as vaginal masses helped in early disease detection.